1. Field of the invention
The invention relates to pharmaceutical composition useful in photodynamic therapy (PDT). In particular, it relates to methods of packaging a hydrophobic photosensitizer (PS) and PS precursors into copolymer liposome formulation to facilitate mucosal uptake of the drug.
2. Information Disclosure Statement
For an effective drug treatment it is important to maintain the drug concentration for a certain period of time at the absorption site and thereby facilitate the uptake of the drug. Drug applied to the mucosal layer (i.e. covering the mucosal epithelial surface) undergoes fast elimination due to the effective clearance mechanism seen in these parts of the body, thus reducing the duration of the therapeutic effect and hence requiring frequent application. When frequent dosing is required, it can result in increased costs and may lead to decreased patient compliance. In an effort to overcome these shortcomings, researchers have looked at improving the delivery systems of pharmaceutical substances. Thus a suitable drug carrier with mucoadhesive properties can improve the effectiveness of drug transfer at the absorption site.
Mucoadhesive drug delivery systems are using the attraction between mucosa cells and the polymeric drug carrier. They provide localization of the drug at the specific body site and increase penetration efficiency of the drug. These features greatly enhance the bioavailability of drugs. Obviously, understanding of mucosa/polymer interactions in the physiological environment is essential for designing mucoadhesive delivery systems.
Drug carriers are frequently used to transport and deliver drugs through the body; they protect the drug against degradation and may extend the circulation time in the bloodstream. Normal cells can be protected from the toxic side effects of the drug, and the drug can be targeted to the site of action. Examples of such carrier are microparticles, drug-polymer conjugates, polymer micelles, liposomes and nanospheres.
Drug carriers can be used to delivery hydrophobic PS and their precursors. The medicament carrier can be composed of natural and or synthetic phospholipids which are capable of forming micelles/liposomes. Hydrophobic Photosensitizers and their precursors are insoluble in water, and therefore when administered they are absorbed by the body before being dissolved thus causing adverse side effects.
Current attempts to delivery water-insoluble substance in medicaments mostly is involve some form of encapsulation or solvent carriers other than water.
While formulating a hydrophobic composition for mucosal application, it is important to use substances which are able to solubilize hydrophobic substances stable at physiological conditions, and most of all are non-irritant to the mucosal cell layer.
Several bioadhesive drugs delivery systems based on a variety of polymers have been described in patents and in the literature. For example, U.S. Pat. No. 6,387,408 by Illum et al. describes the use of adhesive material, ‘adhesin’ derived from bacteria or synthetic analog of the same to combine with a drug entrapped in liposome or emulsion to provide attachment to the gastrointestinal tract. Another example in U.S. Pat. No. 6,428,813 by Akiyama et al. discloses an anti-Helicobacter pylori pharmaceutical agent with enhanced gastrointestinal mucosa-adherent composition to treat gastric and duodenal ulcers.
U.S. Pat. No. 6,582,720 by Inagi et al. also discusses a medicinal composition having adhering capacity to the mucosal layer of stomach and duodenum. Here the drug carrier attaches to the mucosal layer at acidic pH values. In Poly (acrylic acid) (PAA) the adhesive interaction is reduced at pH higher than 5, while mucoadhesive strength of poly (hydroxyethyl methacrylate) (PHEMA) is reduced at pH 1. U.S. Patent Application 2004/0009212 by Tsai describes a thermoresponsive mucoadhesive-carrier composition for topical delivery of PS useful in photodynamic therapy (PDT). US Patent Application 2002/0156062 by Boch et al, discloses use of water soluble microaggregates (e.g. micelles, liposome) for delivering hydrophobic (water insoluble) polypyrrolic macrocyle-based photosensitizers, however the formulation is not specific to mucosal administration.
In the field of PDT, there is a continuing need for a drug delivery system that is simple, non-toxic, chemically inert, and economical and that can easily be used for formulating different types of photosensitizers. Formulations of hydrophobic photosensitizers are required not only to maintain the drug in relatively non-aggregate form, but also to achieve effective delivery to a target site. The formulation should be stable prior to administration, while displaying effective delivery and performance at the target site.
The present invention relates to thermogel formulations of hydrophobic photosensitizers and their precursors, which are incorporated into liposomes to improve delivery of the drug to cells and tissues.